Formation of N-Protected 3,6-bis-(4-aminoalkyl)-2,5,diketopiperazine

ABSTRACT

The disclosed embodiments detail improved methods for the synthesis of diketopiperazines from amino acids. In particular improved methods for the cyclocondensation and purification of N-protected 3,6-(aminoalkyl)-2,5-diketopiperazines from N-protected amino acids. Disclosed embodiments describe methods for the synthesis of 3,6-bis-[N-protected aminoalkyl]-2,5-diketopiperazine comprising heating a mixture of an amino acid in the presence of a catalyst in an organic solvent. The catalyst is selected from the group comprising sulfuric acid, phosphoric acid, p-toluenesulfonic acid, 1-propylphosphonic acid cyclic anhydride, tributyl phosphate, phenyl phosphonic acid and phosphorous pentoxide among others. The solvent is selected from the group comprising: dimethylacetamide, N-methyl-2-pyrrolidone, diglyme, ethyl glyme, proglyme, ethyldiglyme, m-cresol, p-cresol, o-cresol, xylenes, ethylene glycol and phenol among others.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Non-provisional applicationSer. No. 16/866,056, now U.S. Pat. No. 11,440,891, filed May 4, 2020,which is a continuation of U.S. Non-provisional application Ser. No.16/266,683, now U.S. Pat. No. 10,640,471, filed Feb. 4, 2019, which is acontinuation of U.S. Non-provisional application Ser. No. 15/237,427,now U.S. Pat. No. 10,196,366, filed Aug. 15, 2016, which is acontinuation of U.S. Non-provisional application Ser. No. 14/543,464,now U.S. Pat. No. 9,416,113, filed Nov. 17, 2014, which is acontinuation of U.S. Non-provisional application Ser. No. 13/368,172,now U.S. Pat. No. 8,912,328, filed Feb. 7, 2012, which, in turn, claimsthe benefit of U.S. Provisional Application No. 61/441,525 filed on 10Feb. 2011, the content of which are hereby incorporated by reference asif fully recited herein.

TECHNICAL FIELD

The present invention relates to compositions for delivering activeagents, and particularly biologically active agents. Disclosedembodiments are in the field of chemical synthesis and more particularlyare related to improved synthetic methods for the preparation andpurification of 3,6-di-substituted-2,5-diketopiperazines.

BACKGROUND

Drug delivery is a persistent problem in the administration of activeagents to patients. Conventional means for delivering active agents areoften severely limited by biological, chemical, and physical barriers.Typically, these barriers are imposed by the environment through whichdelivery occurs, the environment of the target for delivery, or thetarget itself.

Biologically active agents are particularly vulnerable to such barriers.For example, in the delivery of pharmacological and therapeutic agentsto humans, barriers are imposed by the body. Examples of physicalbarriers are the skin and various organ membranes that must be traversedbefore reaching a target. Chemical barriers include, but are not limitedto, pH variations, lipid bi-layers, and degrading enzymes.

These barriers are of particular significance in the design of oraldelivery systems. Oral delivery of many biologically active agents wouldbe the route of choice for administration to animals if not forbiological, chemical, and physical barriers such as varying pH in thegastrointestinal (GI) tract, powerful digestive enzymes, and activeagent impermeable gastrointestinal membranes. Among the numerous agentswhich are not typically amenable to oral administration are biologicallyactive peptides, such as calcitonin and insulin; polysaccharides, and inparticular mucopolysaccharides including, but not limited to, heparin;heparinoids; antibiotics; and other organic substances. These agents arerapidly rendered ineffective or are destroyed in the gastrointestinaltract by acid hydrolysis, enzymes, or the like.

However, broad spectrum use of drug delivery systems is often precludedbecause: (1) the systems require toxic amounts of adjuvants orinhibitors; (2) suitable low molecular weight active agents are notavailable; (3) the systems exhibit poor stability and inadequate shelflife; (4) the systems are difficult to manufacture; (5) the systems failto protect the active agent; (6) the systems adversely alter the activeagent; or (7) the systems fail to allow or promote absorption of theactive agent.

There is still a need in the art for simple, inexpensive deliverysystems which are easily prepared and which can deliver a broad range ofactive agents. One class of delivery system that has shown promise asexcipients is diketopiperazines (DKP). In particular,3,6-bis-substituted-2,5-diketopiperazines have been shown to effectivelydeliver biologically active agents across the lining of the lung.

Conventional synthesis of diketopiperazines proceeds via acyclocondensation of two amino acid molecules or a dipeptide. Oneexemplary process for the synthesis of diketopiperazines, entailsheating an amino acid (Cbz-L-lysine for example) in m-cresol for between17 and 22 hours at 160-170° C., and recrystallizing the diketopiperazinefrom acetic acid for a yield of about 48%.

U.S. Pat. No. 7,709,639 to Stevenson et. al. details methods for thesynthesis of bis-Cbz-N-protected diketopiperazines, the disclosure ofwhich is hereby incorporated by reference in its entirety as if recitedfully herein.

Others have generated diketopiperazines from isolated dipeptides byheating in an appropriate solvent while removing water by distillation.While these provide the desired diketopiperazines, the methods providesuboptimal yields and may require prolonged purification. Thus, there isa need for an improved method for the synthesis of disubstituted2,5-diketopiperazines that provides the N-protected diketopiperazines ingood yield while preserving the protecting groups and requiring minimalpurification.

SUMMARY

This and other unmet needs of the prior art are met by compounds andmethods as described in more detail below. The use of N-substituted3,6-aminoalkyl-2,5-diketopiperazines as pharmaceutical excipients hasshown considerable promise. As noted above, these compounds are oftensynthesized via cyclocondensation of amino acids. If the amino acid hasa free nitrogen on its side-chain (as in, for example, lysine oromithine) it is often necessary to have this nitrogen blocked prior tothe cyclization reaction. Because of the potential for disparatesynthetic processes after cyclization, compatibility with a variety ofprotecting groups is desired. Thus a synthetic method that canaccommodate a number of diverse N-protecting groups and produce goodyield of N-protected diketopiperazine is desired.

Some useful protecting groups include trifluoroacteyl, acetyl and otheramide forming protecting groups; carbamate protecting groups includingbenzyloxycarbonyl (Cbz) and t-butoxycarbonyl (BOC).

In an embodiment,3,6-bis-4-(N-trifluoroacetyl)aminobutyl-2,5-diketopiperazine is formedby heating F-trifluoroacetyl-L-lysine in a water miscible solvent suchas N-methyl-2-pyrrolidone (NMP) in the presence of a catalyst chosenfrom the group comprising phosphoric acid, sulfuric acid and phosphorouspentoxide to a temperature of about 150-175° C. The diketopiperazine isisolated by quenching with water and filtering the resulting solid.

Disclosed embodiments describe methods for the synthesis of3,6-bis-[N-protected aminoalkyl]-2,5-diketopiperazine comprising heatinga mixture of an amino acid of general formula I in the presence of acatalyst in an organic solvent; wherein the catalyst is selected fromthe group comprising sulfuric acid, phosphoric acid, p-toluenesulfonicacid, 1-propylphosphonic acid cyclic anhydride, tributyl phosphate,phenyl phosphonic acid and phosphorous pentoxide among others; andwherein the solvent is selected from the group comprising:dimethylacetamide, N-methyl-2-pyrrolidone, diglyme, ethyl glyme,proglyme, ethyldiglyme, m-cresol, p-cresol, o-cresol, xylenes, ethyleneglycol and phenol among others.

The disclosed embodiments also describe methods wherein n is betweenfrom 1 to 7, wherein n is equal to 3, wherein n is equal to 2, whereinPG is an amide forming protecting group, wherein the protecting group istrifluoroacetyl, wherein PG is a carbamate forming protecting group,wherein the protecting group is Cbz, wherein the solvent issubstantially water miscible, wherein the solvent isN-methyl-2-pyrrolidone, wherein the amino acid isε-trifluoroacetyl-L-lysine, wherein the amino acid is ε-Cbz-L-lysine,wherein the amino acid is γ-trifluoroacetyl-omithine, wherein the aminoacid is γ-Cbz-omithine, wherein the catalyst is phosphorous pentoxide,wherein the concentration of phosphorous pentoxide is from 10% to about50% that of the amino acid, and embodiments further comprising the stepof quenching the mixture with water.

Disclosed embodiments describe methods for the synthesis of3,6-bis-[N-protected aminobutyl]-2,5-diketopiperazine comprising:heating a mixture of a N-protected lysine in the presence of a catalystin an organic solvent, to a temperature of between 110° and 175° C. forbetween 0.25 and 5 hours; wherein the catalyst is selected from thegroup comprising sulfuric acid, phosphoric acid and phosphorouspentoxide, the concentration of catalyst from about 5% to about 50% thatof the lysine; and the solvent is selected from the group comprising:dimethylacetamide, N-methyl-2-pyrrolidone, diglyme, ethyl glyme,proglyme, ethyldiglyme, m-cresol, p-cresol, o-cresol, xylenes, ethyleneglycol and phenol.

Disclosed embodiments describe methods for the synthesis of3,6-bis-4-(N-trifluoroacetyl)aminobutyl-2,5-diketopiperazine comprising:heating a mixture of ε-trifluoroacetyl-L-lysine in the presence ofphosphorous pentoxide in N-methyl-2-pyrrolidone, to a temperature ofbetween 150° and 175° C. for between 0.25 and 5 hours, the concentrationof phosphorous pentoxide is from about 10% to about 40% that of thelysine; and quenching the mixture with a second solvent, oralternatively, wherein the concentration of phosphorous pentoxide tolysine is between 20% and 35% and the mixture is quenched with water.

Any combination of the above described elements in all possiblevariations thereof is encompassed by the disclosed embodiments unlessotherwise indicated herein or otherwise clearly contradicted by context.

BRIEF DESCRIPTION OF THE DRAWINGS

A better understanding of the exemplary embodiments of the inventionwill be had when reference is made to the accompanying drawings, whereinidentical parts are identified with identical reference numerals, andwherein:

FIG. 1 is a scheme showing the cyclocondensation of an N-protected aminoacid into a diketopiperazine.

FIG. 2 is a scheme showing the cyclocondensation of ε-trifluoroacetyllysine.

FIG. 3 is a scheme showing the cyclocoondensation of γ-Cbz-omithine.

DETAILED DESCRIPTION

As used herein, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl and all bondisomers are to be considered as alkyl. These can be mono- orpoly-substituted with (C1-C8)-alkoxy, (C1-C8)-haloalkyl, OH, halogen,NH₂, NO₂, SH, S—(C1-C8) alkyl. (C2-C8)-alkenyl, with the exception ofmethyl, is understood to mean a (C1-C8)-alkyl group as illustrated abovehaving at least one double bond.

A side-chain group of an α-amino acid is understood to mean thechangeable group on the α-C atom of glycine as the basic amino acid.Natural amino acids are given for example in Bayer-Walter, Lehrbuch derorganischen Chemie, S. Hirzel Verlag, Stuttgart, 22nd edition, page822ff. Preferred synthetic amino acids and protected amino acids areavailable from the Sigma-Aldrich Company. The side chain groups can bederived from those referred to there.

The stated chemical structures relate to all possible stereoisomers thatcan be obtained by varying the configuration of the individual chiralcenters, axes or surfaces, in other words all possible diastereomers aswell as all optical isomers (enantiomers) falling within this group.

Turning to the drawings for a better understanding, FIG. 1 shows ageneral scheme for the synthesis of a disubstituted diketopiperazine.This scheme shows an N-protected amino acid undergoing acyclocondensation with a second amino acid molecule. In this embodiment,PG represents a protecting group for the nitrogen and n may be from 0 to7. It is evident from the scheme that it is necessary when forming adiketopiperazine with an amine on a side chain that the nitrogen(s) mustbe blocked prior to the cyclization reaction or yields will be affectedby unwanted side condensations. Depending on the chemistry that will beperformed after ring formation, a variety of protecting groups aredesired, and thus a method that accommodates many groups is preferred.Some useful protecting groups include trifluoroacteyl, acetyl and otheramide forming protecting groups; carbamate protecting groups includingbenzyloxycarbonyl (Cbz) and t-butoxycarbonyl (BOC).

Known methods of cyclocondensation of amino acids to form DKP employedsolvents such as n-butanol (water miscibility of about 7-8%), whereassolvents such as NMP are more miscible with water allowing a simplewater quench/wash to remove reaction solvent and, if the catalyst hassignificant water solubility, the catalyst, all at once. In anembodiment, the catalyst for the amino acid cyclocondensation is watersoluble allowing a water quench and subsequent removal by filtration.

FIG. 2 illustrates an embodiment wherein PG is trifluoroacetyl and n isequal to 3. Thus, the starting amino acid is F-trifluoroacetyl lysineand the product is3,6-bis-4-(N-trifluoroacetyl)aminobutyl-2,5-diketopiperazine. An exampleof a method for the synthesis of3,6-bis-4-(N-trifluoroacetyl)aminobutyl-2,5-diketopiperazine follows:

EXAMPLES Example 1 and 2

To a 1 L, 3-neck round bottom flask equipped with a nitrogen purge, adistillation apparatus, a mechanical stirrer and a thermocouple with atemperature display, was added: NMP (256 mL), TFA-Lys (125 g, 0.52 mol)and P2O5 (22 g, 0.15 mol). The reaction mixture was heated to 160° C.and held there for 1.5 h. The mixture was then cooled to 100° C. andpoured into DI water. The mixture was then cooled below 25° C. and thesolids were isolated via filtration, washed with DI water and dried invacuo at 50° C. to yield3,6-bis-4-(N-trifluoroacetyl)aminobutyl-2,5-diketopiperazine (65.28 g,56.4%). ¹H-NMR (DMSO-d₆): 1.3 (m, 4H), 1.5 (m, 4H), 1.7 (m, 4H), 3.2 (q,4H), 3.8 (m, 2H), 8.1 (s, 2H), 9.4 (s, 2H). Elemental analysis, calc'dC: 42.86; H: 4.95; N: 12.50; F: 25.42. Found: C: 42.95; H: 4.91; N:12.53; F: 24.99.

To a 100 gallon glass-lined reactor was added N-methyl-2-pyrollidone(200 L) and stirring was started. To the solvent was added TFA-lysine(100 kg, 413 mol) at ambient temperature. To the resulting slurry wasadded phosphorous pentoxide (15.2 kg, 107 mol). The mixture was thenheated to 160° C. for 1 h. After 1 h at 160° C. the mixture was cooledto 100° C. and water (500 L) was added. The resulting mixture was cooledto 25° C. and held there for 90 minutes. The resulting solids werewashed twice with water (265 L each) and isolated by filtration to give3,6-bis-4-(N-trifluoroacetyl)aminobutyl-2,5-diketopiperazine in 50%yield.

A variety of catalysts were examined for the formation ofbis-substituted diketopiperazines. The results of the catalyst surveyare shown in Table 1. A general scheme and example for this surveyfollows:

Example 3

Cbz-lysine (10.0 g), diethylene glycol dimethyl ether (diglyme; 50 mL),and a catalyst were charged to a 250 mL round bottom flask. The mixturewas heated to 160-165° C. for 2.5 hours. The reaction mixture was pouredinto water and cooled to ambient temperature overnight. The precipitatedsolid was isolated by filtration, washed with water, and dried in vacuoat 50° C.

TABLE 1 Catalysts for diketopiperazine synthesis. Catalyst AmountReaction yield P₂O₅ 0.76 g (0.15 eq.) 55% P₂O₅ 1.76 g (0.30 eq.) 45%H₂SO₄ 1.27 mL (0.35 eq.) 55% H₃PO₄ 0.73 mL (0.30 eq.) 65% p-toluenesulfonic 3.39 g (0.50 eq.) 52% acid 1-propylphosphonic 4.54 g (0.20 eq.)79% acid cyclic anhydride tributyl phosphate 2.44 g (0.30 eq.) 89% ethylphosphonic acid 1.18 g (0.30 eq.)  0% phenyl phosphonic 1.13 g (0.20eq.) 78% acid

Sulfuric acid and phosphorous pentoxide (at two concentrations) weresurveyed further for synthesis of3,6-bis-4-(N-trifluoroacetyl)aminobutyl-2,5-diketopiperazine in diglyme.The results are shown in Table 2.

Example 4

TFA-lysine (10.0 g), diethylene glycol dimethyl ether (50 mL), and acatalyst were charged to a 250 mL round bottom flask. The mixture washeated to 160-165° C. for 2.5 hours. The reaction mixture was pouredinto water and cooled to ambient temperature. The precipitated solid wasisolated by filtration, washed with water and dried in vacuo at 50° C.

TABLE 2 Catalysts for TFA-lysine diketopiperazine synthesis. CatalystAmount Reaction yield P₂O₅ 0.88 g (0.15 eq.) 41% P₂O₅ 1.76 g (0.30 eq.)55% H₂SO₄ 0.8 mL (0.35 eq.) 40%

Sulfuric acid and phosphorous pentoxide (at two concentrations) weresurveyed further for synthesis of3,6-bis-4-(N-trifluoroacetyl)aminobutyl-2,5-diketopiperazine indimethylacetamide (DMAc). The results are shown in Table 3.

Example 5

TFA-lysine (25.0 g), dimethylacetamide (125 mL), and a catalyst werecharged to a 250 mL round bottom flask. The mixture was heated to160-165° C. for 2.5 hours. The reaction mixture was cooled to 100° C.,poured into water, and then cooled to ambient temperature. Theprecipitated solid was isolated by filtration, washed with water anddried in vacuo at 50° C. The results are shown in Table 3.

TABLE 3 Catalysts for TFA-lysine diketopiperazine synthesis. CatalystAmount Reaction yield P₂O₅ 2.2 g (0.15 eq.) 35% P₂O₅ 5.13 g (0.35 eq.)50% H₂SO₄ 4.19 g (0.40 eq.) 16%

The use of phosphorous pentoxide was examined for the synthesis of3,6-bis-4-(N-trifluoroacetyl)aminobutyl-2,5-diketopiperazine inN-methyl-2-pyrrolidone (NMP) at different times and temperatures. Theresults are shown in Table 4.

Example 6

TFA-lysine (50 g), N-methyl pyrrolidone (125 mL), and P₂O₅ (8.8 g, 0.3eq.) were charged to a round bottom flask. The mixture was heated to areaction temperature for a reaction time. The reaction mixture wascooled, poured into water, and then cooled to ambient temperature. Theprecipitated solid was isolated by filtration, washed with water anddried in vacuo at 50° C.

TABLE 4 Reaction times and temperatures for TFA- lysine diketopiperazinesynthesis. Reaction temp (° C.) Reaction time Reaction yield 110 0.2519% 110 5 54% 170 0.25 59% 170 5 42%

Example 7

TFA-lysine (10.0 g), m-cresol (22 mL), and P₂O₅ were charged to a 250 mLround bottom flask. The mixture was heated to 160-165° C. for 1 hour.The reaction mixture was cooled to 65° C., poured into a solution of 5%aqueous NaOH and methanol, and then cooled to ambient temperature. Theprecipitated solid was isolated by filtration, washed with water anddried in vacuo at 50° C. Product yield was 12%.

Example 8

TFA-lysine (50.0 g) and ethylene glycol (150 mL) were charged to a 500mL round bottom flask. The mixture was heated to 160-170° C. for 2hours. The reaction mixture was poured into water and cooled to ambienttemperature. The precipitated solid was isolated by filtration, washedwith water and dried in vacuo at 50° C. Product yield was 2%.

Example 9

Cbz-lysine (100.0 g) and ethylene glycol (300 mL) were charged to a 1000mL round bottom flask. The mixture was heated to 160-170° C. for 6hours. The reaction mixture was poured into a mixture of water andmethanol and cooled to ambient temperature. The precipitated solid wasisolated by filtration, washed with water and dried in vacuo at 50° C.Product yield was 64%.

FIG. 3 shows a general scheme for the cyclocondensation ofγ-Cbz-omithine.

Example 10

CBz-omithine (100 g), N-methyl pyrrolidone (194 mL), and P₂O₅ (8 g) werecharged to a 1000 mL round bottom flask. The mixture was heated to160-165° C. for 2 hours. The reaction mixture was poured into water andcooled to ambient temperature. The precipitated solid was isolated byfiltration, washed with methanol and water, and dried in vacuo at 50° C.The product yield was 51%.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about”. Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe following specification and attached claims are approximations thatmay vary depending upon the desired properties sought to be obtained bythe disclosed embodiments. At the very least, and not as an attempt tolimit the application of the doctrine of equivalents to the scope of theclaims, each numerical parameter should at least be construed in lightof the number of reported significant digits and by applying ordinaryrounding techniques. Notwithstanding that the numerical ranges andparameters setting forth the broad scope of the disclosed embodimentsare approximations, the numerical values set forth in the specificexamples are reported as precisely as possible. Any numerical value,however, inherently contains certain errors necessarily resulting fromthe standard deviation found in their respective testing measurements.

The terms “a” and “an” and “the” and similar references used in thecontext of describing the disclosed embodiments (especially in thecontext of the following claims) are to be construed to cover both thesingular and the plural, unless otherwise indicated herein or clearlycontradicted by context.

Recitation of ranges of values herein is merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g. “such as”) provided herein isintended merely to better illuminate the disclosed embodiments and doesnot pose a limitation on the scope of the disclosed embodiments unlessotherwise claimed. No language in the specification should be construedas indicating any non-claimed element essential to the practice of thedisclosed embodiments or any variants thereof.

Groupings of alternative elements or embodiments disclosed herein arenot to be construed as limitations. Each group member may be referred toand claimed individually or in any combination with other members of thegroup or other elements found herein. It is anticipated that one or moremembers of a group may be included in, or deleted from, a group forreasons of convenience and/or patentability. When any such inclusion ordeletion occurs, the specification is herein deemed to contain the groupas modified thus fulfilling the written description of any and allMarkush groups used in the appended claims.

Preferred embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention(s).Of course, variations on the disclosed embodiments will become apparentto those of ordinary skill in the art upon reading the foregoingdescription. The inventors expect skilled artisans to employ suchvariations as appropriate, and the inventors intend for the invention(s)to be practiced otherwise than specifically described herein.Accordingly, this disclosure includes all modifications and equivalentsof the subject matter recited in the claims appended hereto as permittedby applicable law. Moreover, any combination of the above describedelements in all possible variations thereof is encompassed by thedisclosed embodiments unless otherwise indicated herein or otherwiseclearly contradicted by context.

Furthermore, references have been made to patents and printedpublications throughout this specification. Each of the above citedreferences and printed publications are hereby individually incorporatedby reference in their entirety.

Having shown and described an embodiment of the invention, those skilledin the art will realize that many variations and modifications may bemade to affect the described invention and still be within the scope ofthe claimed invention. Additionally, many of the elements indicatedabove may be altered or replaced by different elements which willprovide the same result and fall within the spirit of the claimedinvention. It is the intention, therefore, to limit the invention onlyas indicated by the scope of the claims.

1. An oral delivery system comprising a diketopiperazine according toFormula I, the diketopiperazine synthesized by the method comprising

heating a N-protected amino acid to a temperature of 110° C. to 175° C.in the presence of a catalyst in an organic solvent; wherein n is 0 to3; wherein PG is selected from trifluoroacetyl, CBz, and acetyl; whereinthe catalyst is present in a concentration of 20% to 50% that of theN-protected amino acid.
 2. The oral delivery system of claim 1, whereinn is equal to
 3. 3. The oral delivery system of claim 1, wherein PG istrifluoroacetyl.
 4. The oral delivery system of claim 1, wherein PG isCbz.
 5. The oral delivery system of claim 1, wherein the solvent isN-methyl-2-pyrrolidone.
 6. The oral delivery system of claim 1, whereinthe N-protected amino acid is ε-trifluoroacetyl-L-lysine.
 7. The oraldelivery system of claim 1, wherein the catalyst is selected fromsulfuric acid, phosphoric acid, p-toluenesulfonic acid,1-propylphosphonic acid cyclic anhydride, tributyl phosphate, phenylphosphonic acid and phosphorous pentoxide.
 8. The oral delivery systemof claim 1, wherein the mixture is heated for between 0.25 and 6 hours.9. The oral delivery system of claim 1, wherein the N-protected aminoacid is ε-trifluoroacetyl-L-lysine.
 10. The oral delivery system ofclaim 1, wherein the N-protected amino acid is ε-Cbz-L-lysine.
 11. Theoral delivery system of claim 1, wherein the N-protected amino acid isγ-trifluoroacetyl-omithine.
 12. The oral delivery system of claim 1,wherein the N-protected amino acid is γ-Cbz-omithine.
 13. The oraldelivery system of claim 1, wherein the catalyst is phosphorouspentoxide.
 14. The oral delivery system of claim 13, wherein theconcentration of phosphorous pentoxide is from 20% to 40% that of theN-protected amino acid.
 15. The oral delivery system of claim 13,wherein the concentration of phosphorous pentoxide is from 20% to 35%that of the N-protected amino acid.
 16. The oral delivery system ofclaim 1, further comprising the step of quenching the mixture withwater.
 17. The oral delivery system of claim 1, wherein the mixture isheated to a temperature of between 130° C. and 175° C.
 18. The oraldelivery system of claim 1, wherein the mixture is heated to atemperature of between 150° and 175° C.
 19. The oral delivery system ofclaim 1, wherein the mixture is heated for between 0.25 and 5 hours. 20.An oral delivery system comprising a diketopiperazine according toFormula I, the diketopiperazine synthesized according to the methodcomprising:

heating a mixture of an N-protected amino acid of Formula II in thepresence of a catalyst in an organic solvent;

wherein PG is selected from the group consisting of trifluoroacetyl,CBz, and acetyl, and n is 0 to 3; wherein the catalyst is phosphorouspentoxide, and is present in a concentration of 20% to 35% that of theamino acid; and wherein the solvent is selected from the groupconsisting of: dimethylacetamide, N-methyl-2-pyrrolidone, diglyme, ethylglyme, proglyme, and ethyldiglyme; and wherein the mixture is heated toa temperature of between 150° and 175° C. for between 0.25 and 6 hours.